Diabetic foot lesions (DF) of the lower extremities are a serious and common complication of Diabetes Mellitus Type 2 (NIDDM), and are a health problem, with important socio-economic and health impact, due to large use of material and human resources. They represent one of the most important expenditure items of the health systems of Mexico and all the world also due to increasing of NIDDM. DF according to the International Consensus on Diabetic Foot is an infection, ulceration and/or destruction of deep tissues associated with neurological alterations and varying degrees of peripheral vascular disease in lower extremities that affects patients with NIDDM. Patients with DF often require amputations of the lower extremities and in more than half of the cases, the infection is the predominant factor. The primary cause of DF (diabetic foot), is the damage that the progressive NIDDM produce on the nerves, which is known as neuropathy, that produces decrease or loss of sensitivity to pain, temperature and muscle atrophy, favoring the appearance foot deformities in the bone structures and instability. By decreasing or eliminating sensation in the foot, any wound no matter how small produced by excessive rubbing or increased exposure to heat or cold usually do not manifest itself and the patient does not recognize them properly and without pain that is a defensive mechanism of the organism, diabetics suffer injuries that present progress insidiously. In addition the loss of muscle control causes secondary atrophy in muscles and tendons that favors the appearance of deformities and changes in the distribution of the support of feet during walking and predispose certain points of the foot to develop injuries and wounds which, if not treated in time can be very serious, resulting in osteomyelitis in patients with DF, and once bone is infected, an amputation has to be done and may prove even fatal.
In DF ulcers an infection is confirmed in little more than half of ulcers (52%) while the harmful chronic inflammatory process is invariably present mainly due to the local and systemic insulin resistance.
Ischemia is very frequent in diabetics due to the damage to peripheral vessels and in fact in the EURODIALE study, ischemia was detected in more than 52% of patients suffering from DF. The foot is an area of deficient irrigation since it is very distant to the heart and added to this the damage suffered by blood vessels in NIDD, explains that blood circulation in DF is very decreased. Arterial perfusion is responsible for providing necessary nutrients for tissue regeneration in such a way that if a wound is present, healing will be impeded in NIDDM.
Additionally a decrease in arterial perfusion will not provide an adequate amount of medications prescribed to treat the infection in addition to their questionable efficacy. On the other hand and given the difficulties mentioned, local treatment of the wound is essential though unfortunately may not be effective.
In this regard, in the 2012 Guidelines for Treatment of DF, I.D.S.A. (American Association for Infectious Diseases) issued in November 2012, clearly states that “to date there is no solid evidence of the effectiveness . . . among the products used such as antiseptics, antimicrobials, etc., that are used locally in the treatment of DF . . . and considering that have effects side, toxicity, are expensive and some induce bacterial resistance, cannot be recommended for use. Dumville et al, arrived to similar conclusions in their systematic and extensive review and remarked that local and more expensive treatments had no advantage over the ones used that are less expensive. Another example is the use of the of negative pressure systems (NPWT) that may had mild advantages over the conventional treatments, but that given their price and accessibility cannot be recommended for widespread use.
Vascular ulcers of the lower limbs constitute an important public health problem due to the negative impact in socio-economic and health, for their use of large human and materials resources. Vascular ulcers defined as a lesion with skin loss produced by alterations of the circulation (venous and/or arterial) usually located in the lower third of the pelvic limbs which can develop into chronic ulcers.
According to their etiology, vascular ulcers of can be classified as venous, arterial and mixed. Venous ulcers are caused by a deficiency in microcirculation due to venous hypertension, valvular insufficiency and hypoxia that induces damage in the venous wall and constitute 90% of the all limb ulcers. Arterial ulcers are produced in most of cases by skin ischemia caused by arteriosclerosis and the mixed ones are due to an arteriovenous disorder.
Varicose venous ulcers are the result of a chronic increase in intraluminal hydrostatic pressure due to the failure of the venous valves that produces expansion and tortuosity of the veins, mainly on the pelvic limbs. This situation produces edema and ruptures with extravasation of blood in turn producing dissecting hematomas in soft tissues, all which exerts a direct compressive mechanical action on the skin causing chronic hypoxia, as well as an autolytic destructive process derived from a chronic inflammatory process that prevents healing and this originates the ulcers. These ulcers are characterized by a wide tissue destruction and repeatedly exacerbated by the presence of microorganisms that colonize or infect the wound producing a chronic inflammatory process that increases the ulcer size which can vary in dimension, from a few square centimeters up to large extensions uni or bilaterally.
Currently there is a diversity of therapeutic options for treatment of varicose venous ulcers mainly related to new types of bandages, with or without local and systemic therapeutic agents and with surgical modalities developed by Bioengineering technologies like extracellular matrix and growth factors and various materials for the treatment of the wounds including magistral mixtures of zinc oxide, vaseline, lanolin, starch and silver Sulfadiazine and their use in wounds and in open wounds and their use is widely advertised for due their composition it prevents adhesions to the fatty tissues or foreign bodies and also due to their components may stimulate the healing by granulation. Other materials such as the alginates, the collagen dressings, activated charcoal or silver, the foam polymers, hydrogel hydrocolloids, and polyurethanes that alone or combined with therapeutic schemes may favor venous circulation, keep the injured area aseptic and allow the formation of granulation and epithelization tissue, but none of all the mentioned to date has shown satisfactory consistent results as informed by the American Venous Forum (2011) and the Society of Vascular Surgery of the United States.
On the other hand, it is well known in state of the Art the therapeutic use of starch Hydrosilate film produced agent as described in U.S. Pat. Nos. 3,812,252 and 4,414,202. Hydrolysate starch has bacteriostatic and bactericidal effects.
U.S. Pat. No. 6,046,178 describes a composition for “treatment of external wounds” which includes a hydrolysate starch powder medication with an equivalent of dextrose less than 60, such as a non-hygroscopic maltodextrin, for the treatment of injured or open skin defects as in the case of burns, ulcers, and other types of skin injuries that are exposed to the environmental conditions and pollutants. In another embodiment, starch hidroxilate is mixed with the fluid proteins of the wound to form a film which finally adheres to the underlying tissues, being this film semipermeable to air and liquids.
In order to improve the process of healing of the wound, the composition of the U.S. Pat. No. 6,046,178 is applied in the form of a gel, being the maltodextrin non-hygroscopic, mixed with water and by adding other gelatinizing agents such as per example, Glycerin. In the U.S. Pat. No. 6,046,178 it is also described that water can be added to form a continuous phase emulsion, while the gelatinize is mixed in the continuous phase of such way that this becomes a dispersed phase to form a gel that has a final viscosity in the range of 29,000 to 37,000 cp. The weight percentage of the non-hygroscopic maltodextrin in the composition varies from 57 to 77% for form a continuous aqueous phase. The gel Composition presents advantages or benefits such as for example, an efficient delivery of dermatological agents that have a healing effect and a deeper application of these agents to the wound area. These benefits are provided by the viscosity of the composition, which necessarily requires the addition of Glycerin like an agent of gelatinization in order to provide a viscosity in the range of 29,000 to 37,000 cp. In U.S. Pat. No. 6,046,178 it is recognized that a greater viscosity of the gel of this range, would not disperse in an appropriate way the healing agents to the wound and a minor viscosity of the mentioned range would slip and not be adherent to the wound surface.
Additionally, in the U.S. Pat. No. 6,046,178 includes the use of a dressing for reducing the bacterial inoculum of an infected wound and inhibits the infection of a not infected wound. For this purpose the composition can be mixed with antibacterial agents for the prevention or treatment of a secondary infection. The dressing can be used in external environments for it is semipermeable and it allows the passage of gas and fluids that is to say that the wound can “breathe”, and for that reason has to be changed several times daily. Additionally, a pharmaceutically acceptable metal can be added as a component of the composition to promote growth and development of healthy tissue and thus benefits the healing process. The addition of an additional component can improve the action of the film forming agent combined with the monosaccharide. The optional components generally do not amount to more of the 5% of the total weight of the composition.
U.S. Pat. No. 6,046,178 does not describe that the composition possess anti-inflammatory activity that contributes and favors the healing process of chronic ulcerative lesions such as diabetic foot and varicose venous ulcers.
U.S. Pat. No. 4,600,574 describes a tissue adhesive where a biocompatible material such as a polysaccharide is combined with a solution that contains Fibrinogen and Factor XIII. Due to the presence of fibrin this adhesive has the disadvantages that are described subsequently.
U.S. Pat. No. 5,496,872 describes a not-toxic biodegradable adhesive for surgical use. This composition contains a mixture that possesses at least two different functions that can be used in combination with polypeptides and/or biodegradable polysaccharides, synthetic or natural.
Efforts for developing synthetic polymers have been made such as, by example, cyanoacrylates as adhesives and biomedical sealers. A tissue adhesive is described in U.S. Pat. No. 3,667,472 of Halpern, which is related with the use surgical of adhesives Mono-medic of the drug Agents called alkylating agents of C2-C4 alpha-cyanoacrylate. This tissue adhesives based on cyanoacrylate are polymerized at the contact with water or blood and forms a solid layer crystallized over the tissue layer. However a disadvantage of this kind of adhesives is that is contraindicated for application in internal organs or in vascular surgery due to their toxicity and oncogenic effects that have been well demonstrated.
The well known associated toxicity with synthetic adhesives led the researchers to the development of adhesives biologically derived as materials of union. A type of adhesive or biological derived glue is an adhesive based on fibrin. The commercial tissue adhesives of fibrin are obtained of human plasma which raises the potential for health risks. The fibrin (and its derivatives) have been used in the formulation of biomedical adhesives in a limited manner and with variable results; experimentally and prospective human studies cannot be made for obvious reasons. However, the use of fibrin has various disadvantages: there is the risk of viral transmission like any other cryo-precipitate, processes of extraction blood are required, costs are high, special form of applicators and required and there a substantial risk of allergic reactions. Other disadvantage that have the fibrin-based adhesives is that the force of adhesion is relatively weak compared to the collagen-based adhesives and their cost is very elevated.
More recently, products of combination have been devised to be used as tissue adhesives and sealers. Is has been described the use of a combination of three independently prepared substances, the cryo-precipitate of human Fibrinogen Thrombin in the presence of the calcium ion, and concentrate of factor XIII, in order to obtain a glue for use in biomedical applications. However this type of products and systems of adhesives available do not avoid the health problems produced by the use of products derived of the plasma or blood. Attempts have been made to isolate an analog counterpart of the component that contains Fibrinogen (see, by example, Feldman, M. C., et, Arch Otolaryngoi-Head and Neck Surg (1988) 114:182-185;) Feldman, M. C., et, Arch Opththalmol (1987) 105:963-967; Feldman, M. C., et, M J Otolog (1988) 9:302-305; [Silberstein l. e., et to, Transfusion (1988)-28:319-321]. Nevertheless, the use of preparations of the analog Fibrinogen component also has obvious limitations.
The International application No. PCT/MX2007/000098 entitled “A new adhesive biological biodegradable, not-toxic, for use in abdominal surgery” common property of the inventor of this invention, describes a formula of a not toxic biological adhesive that protects and seals the anastomosis and suture lines in the internal body, cavities, said formula includes dextrin as a dispersion, at least an agent that increases the tack time based in a metal oxide that increases the viscosity and the resistance and the force of adhesion, and optionally an antibiotic; said formula contains 80-97% by weight of dispersion of dextrin, and the dextrin dispersion contains 45 to 75% of solid based in weight total of the formula, and wherein said formula is adequate for prevent dehiscence and strengthens temporarily the anastomosis and suture line on the internal cavities of the body, and prevents the escape of secretions and bacteria. However, the International Application does not describes nor suggests that the adhesive formulation possesses a powerful anti-inflammatory or bacteriostatic effect for external use that enhances and favors the healing process of Chronic ulcerative lesions such as diabetic foot and venous varicose ulcers.
The International Application No. PCT/MX2011/000146 entitled “Biological thixotropic adhesive for use in internal cavities of the body” common property of the inventor of this invention, describes a biological thixotropic adhesive comprising dextrin, and at least a structural component that provides thixotropy to the adhesive, and optionally at least a antibiotic, and is useful to stimulate the healing of tissue in a patient, for example, to prevent dehiscence of an anastomosis in the digestive system of a patient, to fix a prosthesis during a hernia operation in a patient and to occlude a fistula in a patient. The biological thixotropic Adhesive can be used with a patch of fatty tissue. However, the international application does not describe not suggests that the biological thixotropic adhesive possesses a powerful anti-inflammatory or bacteriostatic effect for external use that enhances and favors the process of healing in Chronic Ulcerative lesions such as diabetic foot and varicose venous ulcers.
Therefore there is a need in the state of the art technique for a composition with high anti-inflammatory and bacteriostatic properties for use external in humans. Particularly, there is a need for a composition useful in enhancing and favoring the healing process of Chronic ulcerative lesions such as for example, diabetic foot and varicose venous ulcers which are characterized by a complicated environment with local and systemic chronic inflammation, by lack of circulation, pH abnormalities, toxic bacterial products, necrosis, and foreign body effects.
There is a need for a useful composition to enhance and favor the healing process of Chronic ulcerative lesions such as for example, diabetic foot and varicose venous ulcers, that does not require of an interface, patches, dressings and similar, to help and favor the healing process of Chronic ulcers.